Resveratrol protects retinal ganglion cells against ischemia induced damage by increasing Opa1 expression

Pang,Yulian; Qin,Mengqi; Hu,Piaopiao; Ji,Kaibao; Xiao,Ruihan; Sun,Nan; Pan,Xinghui; Zhang,Xu

doi:10.3892/ijmm.2020.4711

Resveratrol protects retinal ganglion cells against ischemia induced damage by increasing Opa1 expression

Authors:
- Yulian Pang
- Mengqi Qin
- Piaopiao Hu
- Kaibao Ji
- Ruihan Xiao
- Nan Sun
- Xinghui Pan
- Xu Zhang
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Affiliations: Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Jiangxi Provincial Key Laboratory for Ophthalmology, Nanchang, Jiangxi 330006, P.R. China
Published online on: August 27, 2020 https://doi.org/10.3892/ijmm.2020.4711
Pages: 1707-1720
Copyright: © Pang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Loss of idiopathic retinal ganglion cells (RGCs) leads to irreversible vision defects and is considered the primary characteristic of glaucoma. However, effective treatment strategies in terms of RGC neuroprotection remain elusive. In the present study, the protective effects of resveratrol on RGC apoptosis, and the mechanisms underlying its effects were investigated, with a particular emphasis on the function of optic atrophy 1 (Opa1). In an ischemia/reperfusion (I/R) injury model, the notable thinning of the retina, significant apoptosis of RGCs, reduction in Opa1 expression and long Opa1 isoform to short Opa1 isoform ratios (L‑Opa1/S‑Opa1 ratio) were observed, all of which were reversed by resveratrol administration. Serum deprivation resulted in reductions in R28 cell viability, superoxide dismutase (SOD) activity, Opa1 expression and induced apoptosis, which were also partially reversed by resveratrol treatment. To conclude, results from the present study suggest that resveratrol treatment significantly reduced retinal damage and RGC apoptosis in I/R injury and serum deprivation models. In addition, resveratrol reversed the downregulated expression of Opa1 and reduced SOD activity. Mechanistically, resveratrol influenced mitochondrial dynamics by regulating the L‑Opa1/S‑Opa1 ratio. Therefore, these observations suggest that resveratrol may exhibit potential as a therapeutic agent for RGC damage in the future.

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1	Bonomi L: Epidemiology of angle-closure glaucoma. Acta Ophthalmol Scand Suppl. 236:11–13. 2002. View Article : Google Scholar : PubMed/NCBI
2	Garcia-Valenzuela E, Shareef S, Walsh J and Sharma SC: Programmed cell death of retinal ganglion cells during experimental glaucoma. Exp Eye Res. 61:33–44. 1995. View Article : Google Scholar : PubMed/NCBI
3	Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ and Zack DJ: Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 36:774–786. 1995.PubMed/NCBI
4	Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL and Di Polo A: The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res. 31:152–181. 2012. View Article : Google Scholar
5	Williams PA, Harder JM, Foxworth NE, Cochran KE, Philip VM, Porciatti V, Smithies O and John SW: Vitamin B₃ modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science. 355:756–760. 2017. View Article : Google Scholar : PubMed/NCBI
6	Huang C, Zhang P, Wang W, Xu Y, Wang M, Chen X and Dong X: Long-term blue light exposure induces RGC-5 cell death in vitro: Involvement of mitochondria-dependent apoptosis, oxidative stress, and MAPK signaling pathways. Apoptosis. 19:922–932. 2014. View Article : Google Scholar : PubMed/NCBI
7	Das A, Bell CM, Berlinicke CA, Marsh-Armstrong N and Zack DJ: Programmed switch in the mitochondrial degradation pathways during human retinal ganglion cell differentiation from stem cells is critical for RGC survival. Redox Biol. 34:1014652020. View Article : Google Scholar : PubMed/NCBI
8	Giacomello M, Pyakurel A, Glytsou C and Scorrano L: The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol. 21:204–224. 2020. View Article : Google Scholar : PubMed/NCBI
9	Lee S, Van Bergen NJ, Kong GY, Chrysostomou V, Waugh HS, O'Neill EC, Crowston JG and Trounce IA: Mitochondrial dysfunction in glaucoma and emerging bioenergetic therapies. Exp Eye Res. 93:204–212. 2011. View Article : Google Scholar
10	Schober MS, Chidlow G, Wood JP and Casson RJ: Bioenergetic-based neuroprotection and glaucoma. Clin Exp Ophthalmol. 36:377–385. 2008. View Article : Google Scholar : PubMed/NCBI
11	Dhingra A, Jayas R, Afshar P, Guberman M, Maddaford G, Gerstein J, Lieberman B, Nepon H, Margulets V, Dhingra R and Kirshenbaum LA: Ellagic acid antagonizes Bnip3-mediated mitochondrial injury and necrotic cell death of cardiac myocytes. Free Radic Biol Med. 112:411–422. 2017. View Article : Google Scholar : PubMed/NCBI
12	Geng J, Wei M, Yuan X, Liu Z, Wang X, Zhang D, Luo L, Wu J, Guo W and Qin ZH: TIGAR regulates mitochondrial functions through SIRT1-PGC1 α pathway and translocation of TIGAR into mitochondria in skeletal muscle. FASEB J. 33:6082–6098. 2019. View Article : Google Scholar : PubMed/NCBI
13	Sun Y, Xue W, Song Z, Huang K and Zheng L: Restoration of Opa1-long isoform inhibits retinal injury-induced neurodegeneration. J Mol Med (Berl). 94:335–346. 2016. View Article : Google Scholar
14	Youle RJ and van der Bliek AM: Mitochondrial fission, fusion, and stress. Science. 337:1062–1065. 2012. View Article : Google Scholar : PubMed/NCBI
15	Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS, Danial NN, De Strooper B and Scorrano L: OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell. 126:177–189. 2006. View Article : Google Scholar : PubMed/NCBI
16	Baur JA and Sinclair DA: Therapeutic potential of resveratrol: The in vivo evidence. Nat Rev Drug Discov. 5:493–506. 2006. View Article : Google Scholar : PubMed/NCBI
17	Chong ZZ, Shang YC, Wang S and Maiese K: SIRT1: new avenues of discovery for disorders of oxidative stress. Expert Opin Ther Targets. 16:167–178. 2012. View Article : Google Scholar : PubMed/NCBI
18	Ahmed T, Javed S, Javed S, Tariq A, Šamec D, Tejada S, Nabavi SF, Braidy N and Nabavi SM: Resveratrol and Alzheimer's disease: Mechanistic insights. Mol Neurobiol. 54:2622–2635. 2017. View Article : Google Scholar
19	Pandey AK, Bhattacharya P, Shukla SC, Paul S and Patnaik R: Resveratrol inhibits matrix metalloproteinases to attenuate neuronal damage in cerebral ischemia: A molecular docking study exploring possible neuroprotection. Neural Regen Res. 10:568–575. 2015. View Article : Google Scholar : PubMed/NCBI
20	Richard T, Pawlus AD, Iglésias ML, Pedrot E, Waffo-Teguo P, Mérillon JM and Monti JP: Neuroprotective properties of resveratrol and derivatives. Ann N Y Acad Sci. 1215:103–108. 2011. View Article : Google Scholar : PubMed/NCBI
21	Abu-Amero KK, Kondkar AA and Chalam KV: Resveratrol and ophthalmic diseases. Nutrients. 8:2002016. View Article : Google Scholar : PubMed/NCBI
22	Zuo L, Khan RS, Lee V, Dine K, Wu W and Shindler KS: SIRT1 promotes RGC survival and delays loss of function following optic nerve crush. Invest Ophthalmol Vis Sci. 54:5097–5102. 2013. View Article : Google Scholar : PubMed/NCBI
23	Krishnamoorthy RR, Agarwal P, Prasanna G, Vopat K, Lambert W, Sheedlo HJ, Pang IH, Shade D, Wordinger RJ, Yorio T, et al: Characterization of a transformed rat retinal ganglion cell line. Brain Res Mol Brain Res. 86:1–12. 2001. View Article : Google Scholar : PubMed/NCBI
24	Liu B, Chen H, Johns TG and Neufeld AH: Epidermal growth factor receptor activation: An upstream signal for transition of quiescent astrocytes into reactive astrocytes after neural injury. J Neurosci. 26:7532–7540. 2006. View Article : Google Scholar : PubMed/NCBI
25	Bennet D and Kim S: Effects of agmatine and resveratrol on RGC-5 cell behavior under light stimulation. Environ Toxicol Pharmacol. 38:84–97. 2014. View Article : Google Scholar : PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
27	Chintala SK, Zhang X, Austin JS and Fini ME: Deficiency in matrix metalloproteinase gelatinase B (MMP-9) protects against retinal ganglion cell death after optic nerve ligation. J Biol Chem. 277:47461–47468. 2002. View Article : Google Scholar : PubMed/NCBI
28	Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, et al: Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 127:1109–1122. 2006. View Article : Google Scholar : PubMed/NCBI
29	Anderson CJ, Kahl A, Fruitman H, Qian L, Zhou P, Manfredi G and Iadecola C: Prohibitin levels regulate OMA1 activity and turnover in neurons. Cell Death Differ. 27:1896–1906. 2020. View Article : Google Scholar
30	Griparic L, Kanazawa T and van der Bliek AM: Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol. 178:757–764. 2007. View Article : Google Scholar : PubMed/NCBI
31	Osborne NN, Casson RJ, Wood JP, Chidlow G, Graham M and Melena J: Retinal ischemia: Mechanisms of damage and potential therapeutic strategies. Prog Retin Eye Res. 23:91–147. 2004. View Article : Google Scholar : PubMed/NCBI
32	Gao H, Zhang HL, Shou J, Chen L, Shen Y, Tang Q, Huang J and Zhu J: Towards retinal ganglion cell regeneration. Regen Med. 7:865–875. 2012. View Article : Google Scholar : PubMed/NCBI
33	Semba RD, Ferrucci L, Bartali B, Urpí-Sarda M, Zamora-Ros R, Sun K, Cherubini A, Bandinelli S and Andres-Lacueva C: Resveratrol levels and all-cause mortality in older community-dwelling adults. JAMA Intern Med. 174:1077–1084. 2014. View Article : Google Scholar : PubMed/NCBI
34	Zhang X, Feng Y, Wang Y, Wang J, Xiang D, Niu W and Yuan F: Resveratrol ameliorates disorders of mitochondrial biogenesis and dynamics in a rat chronic ocular hypertension model. Life Sci. 207:234–245. 2018. View Article : Google Scholar : PubMed/NCBI
35	Lindsey JD, Duong-Polk KX, Hammond D, Leung CK and Weinreb RN: Protection of injured retinal ganglion cell dendrites and unfolded protein response resolution after long-term dietary resveratrol. Neurobiol Aging. 36:1969–1981. 2015. View Article : Google Scholar : PubMed/NCBI
36	Szabo ME, Droy-Lefaix MT, Doly M and Braquet P: Free radical-mediated effects in reperfusion injury: A histologic study with superoxide dismutase and EGB 761 in rat retina. Ophthalmic Res. 23:225–234. 1991. View Article : Google Scholar : PubMed/NCBI
37	Belforte N, Sande PH, de Zavalia N, Fernandez DC, Silberman DM, Chianelli MS and Rosenstein RE: Ischemic tolerance protects the rat retina from glaucomatous damage. PLoS One. 6:e237632011. View Article : Google Scholar : PubMed/NCBI
38	Seigel GM: Review: R28 retinal precursor cells: The first 20 years. Mol Vis. 20:301–306. 2014.PubMed/NCBI
39	Charles I, Khalyfa A, Kumar DM, Krishnamoorthy RR, Roque RS, Cooper N and Agarwal N: Serum deprivation induces apoptotic cell death of transformed rat retinal ganglion cells via mitochondrial signaling pathways. Invest Ophthalmol Vis Sci. 46:1330–1338. 2005. View Article : Google Scholar : PubMed/NCBI
40	Lee SB, Kim JJ, Kim TW, Kim BS, Lee MS and Yoo YD: Serum deprivation-induced reactive oxygen species production is mediated by Romo1. Apoptosis. 15:204–218. 2010. View Article : Google Scholar
41	Liu Q, Ju WK, Crowston JG, Xie F, Perry G, Smith MA, Lindsey JD and Weinreb RN: Oxidative stress is an early event in hydrostatic pressure induced retinal ganglion cell damage. Invest Ophthalmol Vis Sci. 48:4580–4589. 2007. View Article : Google Scholar : PubMed/NCBI
42	Kang KD, Andrade da Costa BL and Osborne NN: Stimulation of prostaglandin EP2 receptors on RGC-5 cells in culture blunts the negative effect of serum withdrawal. Neurochem Res. 35:820–829. 2010. View Article : Google Scholar : PubMed/NCBI
43	Kvanta A, Seregard S, Sejersen S, Kull B and Fredholm BB: Localization of adenosine receptor messenger. RNAs in the rat eye Exp Eye Res. 65:595–602. 1997. View Article : Google Scholar
44	Grillo SL, McDevitt DS, Voas MG, Khan AS, Grillo MA and Stella SJ Jr: Adenosine receptor expression in the adult zebrafish retina. Purinergic Signal. 15:327–342. 2019. View Article : Google Scholar : PubMed/NCBI
45	Castillo A, Tolón MR, Fernández-Ruiz J, Romero J and Martinez-Orgado J: The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol Dis. 37:434–440. 2010. View Article : Google Scholar
46	Dai SS, Zhou YG, Li W, An JH, Li P, Yang N, Chen XY, Xiong RP, Liu P, Zhao Y, et al: Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury. J Neurosci. 30:5802–5810. 2010. View Article : Google Scholar : PubMed/NCBI
47	Von Lubitz DK, Lin RC, Popik P, Carter MF and Jacobson KA: Adenosine A3 receptor stimulation and cerebral ischemia. Eur J Pharmacol. 263:59–67. 1994. View Article : Google Scholar : PubMed/NCBI
48	Kressel M and Groscurth P: Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA. Cell Tissue Res. 278:549–556. 1994. View Article : Google Scholar : PubMed/NCBI
49	Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI
50	Hass DT and Barnstable CJ: Mitochondrial uncoupling protein 2 knock-out promotes mitophagy to decrease retinal ganglion cell death in a mouse model of glaucoma. J Neurosci. 39:3582–3596. 2019.PubMed/NCBI
51	Olichon A, Guillou E, Delettre C, Landes T, Arnauné-Pelloquin L, Emorine LJ, Mils V, Daloyau M, Hamel C, Amati-Bonneau P, et al: Mitochondrial dynamics and disease OPA1. Biochim Biophys Acta. 1763:500–509. 2006. View Article : Google Scholar : PubMed/NCBI
52	Shalaeva DN, Dibrova DV, Galperin MY and Mulkidjanian AY: Modeling of interaction between cytochrome c and the WD domains of Apaf-1: Bifurcated salt bridges underlying apopto-some assembly. Biol Direct. 10:292015. View Article : Google Scholar
53	Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P and Lenaers G: Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem. 278:7743–7746. 2003. View Article : Google Scholar : PubMed/NCBI
54	Varanita T, Soriano ME, Romanello V, Zaglia T, Quintana-Cabrera R, Semenzato M, Menabò R, Costa V, Civiletto G, Pesce P, et al: The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell Metab. 21:834–844. 2015. View Article : Google Scholar : PubMed/NCBI
55	Zhang L, He Z, Zhang Q, Wu Y, Yang X, Niu W, Hu Y and Jia J: Exercise pretreatment promotes mitochondrial dynamic protein OPA1 expression after cerebral ischemia in rats. Int J Mol Sci. 15:4453–4463. 2014. View Article : Google Scholar : PubMed/NCBI
56	Williams PA, Morgan JE and Votruba M: Opa1 deficiency in a mouse model of dominant optic atrophy leads to retinal ganglion cell. dendropathy Brain. 133:2942–2951. 2010. View Article : Google Scholar
57	Hu X, Dai Y, Zhang R, Shang K and Sun X: Overexpression of optic atrophy type 1 protects retinal ganglion cells and upregu-lates Parkin expression in experimental glaucoma. Front Mol Neurosci. 11:3502018. View Article : Google Scholar
58	Jardim FR, de Rossi FT, Nascimento MX, da Silva Barros RG, Borges PA, Prescilio IC and de Oliveira MR: Resveratrol and brain mitochondria:. A review Mol Neurobiol. 55:2085–2101. 2018. View Article : Google Scholar
59	de Oliveira MR, Nabavi SF, Manayi A, Daglia M, Hajheydari Z and Nabavi SM: Resveratrol and the mitochondria: From triggering the intrinsic apoptotic pathway to inducing mitochondrial biogenesis, a mechanistic view. Biochim Biophys Acta. 1860:727–745. 2016. View Article : Google Scholar : PubMed/NCBI
60	Peng K, Tao Y, Zhang J, Wang J, Ye F, Dan G, Zhao Y, Cai Y, Zhao J, Wu Q, et al: Resveratrol regulates mitochondrial biogenesis and fission/fusion to attenuate rotenone-induced neurotoxicity. Oxid Med Cell Longev. 2016:67056212016. View Article : Google Scholar : PubMed/NCBI
61	Lee H, Smith SB, Sheu SS and Yoon Y: The short variant of optic atrophy 1 (OPA1) improves cell survival under oxidative stress. J Biol Chem. 295:6543–6560. 2020. View Article : Google Scholar : PubMed/NCBI
62	MacVicar T and Langer T: OPA1 processing in cell death and disease-the long and short of it. J Cell Sci. 129:2297–2306. 2016. View Article : Google Scholar : PubMed/NCBI
63	Lang A, Anand R, Altinoluk-Hambüchen S, Ezzahoini H, Stefanski A, Iram A, Bergmann L, Urbach J, Böhler P, Hänsel J, et al: SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy. Aging (Albany NY). 9:2163–2189. 2017. View Article : Google Scholar
64	Alavi MV: Targeted OMA1 therapies for cancer. Int J Cancer. 145:2330–2341. 2019. View Article : Google Scholar : PubMed/NCBI
65	Ishihara N, Fujita Y, Oka T and Mihara K: Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J. 25:2966–2977. 2006. View Article : Google Scholar : PubMed/NCBI
66	Song Z, Chen H, Fiket M, Alexander C and Chan DC: OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol. 178:749–755. 2007. View Article : Google Scholar : PubMed/NCBI
67	Rainbolt TK, Lebeau J, Puchades C and Wiseman RL: Reciprocal degradation of YME1L and OMA1 adapts mitochondrial proteo-lytic activity during stress. Cell Rep. 14:2041–2049. 2016. View Article : Google Scholar : PubMed/NCBI
68	Stiburek L, Cesnekova J, Kostkova O, Fornuskova D, Vinsova K, Wenchich L, Houstek J and Zeman J: YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation. Mol Biol Cell. 23:1010–1023. 2012. View Article : Google Scholar : PubMed/NCBI
69	Rainbolt TK, Saunders JM and Wiseman RL: YME1L degradation reduces mitochondrial proteolytic capacity during oxidative stress. EMBO Rep. 16:97–106. 2015. View Article : Google Scholar :
70	Singh LN, Crowston JG, Lopez Sanchez MIG, Van Bergen NJ, Kearns LS, Hewitt AW, Yazar S, Mackey DA, Wallace DC and Trounce IA: Mitochondrial DNA variation and disease susceptibility in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 59:4598–4602. 2018. View Article : Google Scholar : PubMed/NCBI
71	Kumar M, Tanwar M, Faiq MA, Pani J, Shamsi MB, Dada T and Dada R: Mitochondrial DNA nucleotide changes in primary congenital glaucoma patients. Mol Vis. 19:220–230. 2013.PubMed/NCBI
72	Garcia I, Innis-Whitehouse W, Lopez A, Keniry M and Gilkerson R: Oxidative insults disrupt OPA1-mediated mitochondrial dynamics in cultured mammalian cells. Redox Rep. 23:160–167. 2018. View Article : Google Scholar : PubMed/NCBI
73	Kondadi AK, Anand R and Reichert AS: Functional interplay between cristae biogenesis, mitochondrial dynamics and mitochondrial DNA integrity. Int J Mol Sci. 20:43112019. View Article : Google Scholar :
74	Chen S, Fan Q, Li A, Liao D, Ge J, Laties AM and Zhang X: Dynamic mobilization of PGC-1α mediates mitochondrial biogenesis for the protection of RGC-5 cells by resveratrol during serum deprivation. Apoptosis. 18:786–799. 2013. View Article : Google Scholar : PubMed/NCBI
75	Kim MJ, Chi BH, Yoo JJ, Ju YM, Whang YM and Chang IH: Structure establishment of three-dimensional (3D) cell culture printing model for bladder cancer. PLoS One. 14:e2236892019.
76	Liang T, Tao Q, Guan R, Cao G, Shen H, Liu Z and Xia Q: Antioxidant and antiproliferative activities of cyanidin-3-O-glu-coside (C3G) liposome in Caco-2 cells cultivated in 2D and 3D cell culture models. J Food Sci. 84:1638–1645. 2019. View Article : Google Scholar : PubMed/NCBI
77	Burd A, Kwok CH, Hung SC, Chan HS, Gu H, Lam WK and Huang L: A comparative study of the cytotoxicity of silver-based dressings in monolayer cell, tissue explant, and animal models. Wound Repair Regen. 15:94–104. 2007. View Article : Google Scholar : PubMed/NCBI
78	Li D, Ni S, Miao KS and Zhuang C: PI3K/Akt and caspase pathways mediate oxidative stress-induced chondrocyte apoptosis. Cell Stress Chaperones. 24:195–202. 2019. View Article : Google Scholar :
79	Fukai T and Ushio-Fukai M: Superoxide dismutases: Role in redox signaling, vascular function, and diseases. Antioxid Redox Signal. 15:1583–1606. 2011. View Article : Google Scholar : PubMed/NCBI
80	Chen WM, Shaw LH, Chang PJ, Tung SY, Chang TS, Shen CH, Hsieh YY and Wei KL: Hepatoprotective effect of resveratrol against ethanol-induced oxidative stress through induction of superoxide dismutase in vivo and in vitro. Exp Ther Med. 11:1231–1238. 2016. View Article : Google Scholar : PubMed/NCBI
81	Tomé-Carneiro J, Larrosa M, González-Sarrías A, Tomás-Barberán FA, García-Conesa MT and Espín JC: Resveratrol and clinical trials: The crossroad from in vitro studies to human evidence. Curr Pharm Des. 19:6064–6093. 2013. View Article : Google Scholar : PubMed/NCBI